Abstract
The activation of nuclear factor kappa B (NF-κB) signaling has a central role in the development of adult T-cell leukemia/lymphoma (ATL) and many other cancers. However, the activation mechanism of the NF-κB pathways remains poorly understood. Recently, we reported that N-myc downstream-regulated gene 2 (NDRG2) is a negative regulator of the phosphoinositide 3-kinase (PI3K)/AKT pathway by promoting the active dephosphorylated form of PTEN at its C-terminus via the recruitment of PP2A. Additionally, the down-regulation of NDRG2 expression promotes the inactive phosphorylated form of PTEN, which results in constitutively active PI3K/AKT signaling in various cancer cell types. Here, we investigated the involvement of NDRG2 in modulating NF-κB signaling. The forced expression of NDRG2 in ATL cells down-regulates not only the canonical pathway by inhibiting AKT signaling but also the non-canonical pathway by inducing NF-κB-inducing kinase (NIK) dephosphorylation via the recruitment of PP2A. Therefore, NDRG2 works as a PP2A recruiter to suppress not only PI3K/AKT signaling but also NF-κB signaling, which is particularly important in host defenses or immune responses to Human T-cell leukemia virus type 1 (HTLV-1) infection. Furthermore, the loss of NDRG2 expression might play an important role in the progression of tumor development after HTLV-1 infection.
Highlights
nuclear factor kappa B (NF-κ B) comprises a family of transcription factors that play critical roles in inflammation, immunity, cell proliferation, differentiation, survival and cancer development[6,7]
We recently showed that N-myc downstream-regulated gene 2 (NDRG2) regulates the phosphorylation status of PTEN at its C-terminus by recruiting phosphatase 2A (PP2A) and suppresses phosphoinositide 3-kinase (PI3K)/AKT signaling by dephosphorylating PTEN, the active form of PIP3 phosphatase[15]
Because the loss of NDRG2 expression was found in the majority of OSCC22, we examined the effects of NDRG2 on the stimuli-induced canonical and/or non-canonical NF-κ B pathways in cancer cells by establishing stable NDRG2expressing (NDRG2) or mock clone (Mock) oral squamous cell carcinoma (OSCC) cell lines (SAS and HSC3) after transfecting with an NDRG2-expressing plasmid or a Mock vector, as a control (Fig. 1a and supplementary Fig. S1a)
Summary
NF-κ B comprises a family of transcription factors that play critical roles in inflammation, immunity, cell proliferation, differentiation, survival and cancer development[6,7]. The activation of NF-κ B by Tax is mediated by the direct binding of Tax to the regulatory subunit of I-κ B kinase (IKK) NF-κ B essential modulator (NEMO), which is known as IKKγ This interaction results in the constitutive activation of IKKα and IKKβ , the degradation of all I-κ Bs, and the activation of both the canonical and non-canonical NF-κ B pathways. In the non-canonical pathway, NDRG2 expression dephosphorylates NIK, which is overexpressed and highly phosphorylated (active) in ATL, through the recruitment of PP2A. NDRG2 works as a recruiter of PP2A to suppress the important signaling pathways for defending against infection or immune responses, and the loss of NDRG2 expression might play an important role in the progression of tumor development
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